TLR4 knockout upregulates the expression of Mfn2 and PGC-1α in a high-fat diet and ischemia-reperfusion mice model of liver injury

Abstract

Aims: Patients with nonalcoholic fatty liver disease (NAFLD) have less tolerance to ischemia-reperfusion injury (IRI) of the liver than those with the healthy liver; hence have a higher incidence of severe complications after surgery. This study aimed to investigate the dynamics of the liver and mitochondrial damage and the impact of TLR4 knockout (TLR4KO) on Mfn2 expression in the composite model of NAFLD and IRI.

Main methods: We performed high-fat diet (HFD) feeding and ischemia reperfusion (IR) on wild type (WT) and TLR4 knockout TLR4KO mice.

Key findings: The degree of structural and functional injuries to the liver and mitochondria (NAFLD and IRI) is greater than that caused by a single factor (NAFLD or IRI) or a simple superposition of both. The IL-6 and TNF-α expressions were significantly suppressed (P < .05), while PGC-1α and Mfn2 expressions were up-regulated considerably (P < .05) after TLR4KO. Furthermore, mitochondrial fusion increased, while ATP consumption and ROS production decreased significantly after TLR4KO (P < .05). The degree of reduction of compound injury by TLR4KO is more significant than the reduction degree of single factor injury. Also, TNF-α and IL-6 levels can be used predictive markers for mitochondrial damage and liver tolerance to NAFLD and IRI.

Significance: TLR4KO upregulates the expression of Mfn2 and PGC-1α in the composite model of NAFLD and IRI. This pathway may be related to IL-6 and TNF-α. This evidence provides theoretical and experimental basis for the subsequent Toll-like receptor 4 (TLR4) receptor targeted therapy.

Keywords: Interleukin-6 (IL-6); Ischemia-reperfusion injury (IRI); Mitochondria; Mitofusion2 (Mfn2); Nonalcoholic fatty liver disease (NAFLD); Toll-like receptor 4 (TLR4); Tumor necrosis factor-α (TNF-α).